The present invention relates to antibacterial agents of the carbapenem class in which the five membered ring of the carbapenem nucleus is fused to a biphenyl group which is substituted with various neutral substituents. The fused ring compounds are described in detail below.
Thienamycin was an early carbapenem antibacterial agent having a broad spectrum; it has the following formula: ##STR2## Later, N-formimidoyl thienamycin was discovered; it has the formula: ##STR3##
U.S. Pat. Nos. 5,011,832 and 5,025,006 relate to carbapenems of the structure shown below which exhibit antimicrobial activity against strains of methicillin resistant staphylococci (MRSA). The carbapenems described therein possess a meta-disposed biphenyl moiety attached to the C-2 position of the carbapenem ring. ##STR4##
U.S. Pat. Nos. 4,374,849 and 4,374,879 issued on Feb. 22, 1983 to Christensen, et al. relate to compounds of the formula: ##STR5##
In U.S. Pat. No. 4,374,878, the R group noted above represents a hydroxy substituted ethyl group.
More recently, carbapenem antibacterial agents have been described which have a 2-substituent which is an aryl moiety optionally substituted by, e.g., aminomethyl and substituted aminomethyl. These agents are described in U.S. Pat. Nos. 4,543,257 and 4,260,627 and have the formula: ##STR6## have been disclosed in EPO 422,596 A3 published on Apr. 17, 1991. European Publication No. 416 953 A3 published on Mar. 13, 1991 addresses compounds of the formula: ##STR7##
European Publication No. 517 065 A1 published on Dec. 9, 1992 addresses compounds of the formula: ##STR8##
The carbapenems of the present invention are useful against gram positive microorganisms, especially methicillin resistant Staphylococcus aureus (MRSA), methicillin resistant Staphylococcus epidermidis (MRSE), and methicillin resistant coagulase negative Staphylococci (MRCNS). The antibacterial compounds of the present invention thus comprise an important contribution to therapy of these difficult to control pathogens.
Moreover, there is an increasing need for agents effective against such pathogens (MRSA/MRCNS) which are at the same time safe, i.e., relatively free from undesirable side effects. And, the current agent of choice, vancomycin, a glycopeptide antibacterial, is experiencing an ever increasing amount of resistance in the MRSA/MRCNS pathogens.